IL-24 induces apoptosis of chronic lymphocytic leukemia B cells engaged into the cell cycle through dephosphorylation of STAT3 and stabilization of p53 expression.
Chronic lymphocytic leukemia (CLL) is characterized by the accumulation of long-lived monoclonal B cells mostly arrested at the G(0)/G(1) phase of the cell cycle. CLL cells strongly express intracellular melanoma differentiation-associated gene-7 (MDA7)/IL-24. However, adenovirus-delivered MDA7 was reported to be cytotoxic in several tumor cell lines. We report herein that rIL-24 alone had no effect; however, sequential incubation with rIL-2 and rIL-24 reduced thymidine incorporation by 50% and induced apoptosis of CLL cells in S and G(2)/M phases of the cell cycle, but not of normal adult blood or tonsil B cells. IL-24 stimulated STAT3 phosphorylation in IL-24R1-transfected cells but not in normal or CLL B cells. In contrast, IL-24 reversed the IL-2-induced phosphorylation of STAT3 in CLL, and this effect was neutralized by anti-IL-24 Ab. Phospho- (P)STAT3 inhibition induced by IL-24 was reversed by pervanadate, an inhibitor of tyrosine phosphatases. The addition of rIL-24 to IL-2-activated CLL B cells resulted in increases of transcription, protein synthesis. and phosphorylation of p53. The biological effects of IL-24 were reversed by the p53 inhibitor pifithrin-alpha and partly by the caspase inhibitor zvad. Troglitazone (a protein tyrosine phosphatase, PTP1B activator) phosphatase inhibited PSTAT3 and augmented p53 expression. PSTAT3 is a transcriptional repressor of p53, and therefore IL-24 induction of p53 secondary to PSTAT3 dephosphorylation may be sensed as a stress signal and promote apoptosis in cycling cells. This model explains why IL-24 can protect some resting/differentiated cells and be deleterious to proliferating cells.
Sainz-Perez
Alexander
A
Institut National de la Santé et de la Recherche Médicale U764, IFR 13, Université Paris XI, Clamart, France.
Gary-Gouy
Hélène
H
Gaudin
Françoise
F
Maarof
Ghyath
G
Marfaing-Koka
Anne
A
de Revel
Thierry
T
Dalloul
Ali
A
D000328:Adult; D017209:Apoptosis / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D002453:Cell Cycle / Q000276:immunology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D006801:Humans; D007376:Interleukin-2 / Q000037:antagonists & inhibitors / Q000502:physiology; D007378:Interleukins / Q000502:physiology*; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D008213:Lymphocyte Activation / Q000276:immunology; D010766:Phosphorylation / Q000276:immunology; D011994:Recombinant Proteins / Q000494:pharmacology; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D013936:Thymidine / Q000037:antagonists & inhibitors / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism*; D000099180:Interleukin-24
D007376:Interleukin-2; D007378:Interleukins; D011994:Recombinant Proteins; D050796:STAT3 Transcription Factor; D013936:Thymidine; D016159:Tumor Suppressor Protein p53; D000099180:Interleukin-24; C494086:STAT3 protein, human